Il modulatore epigenetico JQ1 regola l'accumulo di lipidi nel tessuto adiposo bianco inducendo la lipolisi

Adipose tissue is composed of many cell types, but adipocytes make up the bulk of fatty tissue in most animals. They can be divided in three subtypes: white, brown and beige adipocytes, which differ mainly in cell function, body location and size of lipid droplets. Among them, white adipocytes are known to have a main role in long-term storage of energy in the form of intracellular lipid droplets. White adipose tissue (WAT) is endowed with a metabolic plasticity and it has an essential role in the maintenance of whole-body homeostasis, satisfying the organism energy needs. Depending on the situation, it can switch between two opposing metabolic programs: lipogenesis, which drives nutrient uptake to store fats when there is a positive energy balance, and lipolysis, which is responsible of nutrient release through fatty acids oxidation in case of energy depletion. Assuming this, we can easily understand how fundamental the pathways that regulate lipid storage and release in adipose tissue are. Therefore, in this study we focused on an epigenetic modulator, known as JQ1, which in many studies was seen able to act in the modulation of lipid homeostasis. It is a cell permeable small molecule that binds competitively to bromodomains of bromodomain extra-terminal domain (BET) proteins, which were shown to be an interesting target to study, given its involvement in many important cellular pathways. JQ1 had already been used in a preliminary in vivo experiment previously carried out in our laboratory, aimed to test the efficacy of this small inhibitor in delaying sarcopenia in old C57/BL6 mouse. These animals were also predisposed to lipid accumulation, and during the JQ1 treatment it has also been seen to exert an effect at the level of white adipose tissue mass, significantly reducing it. Starting from these data, we decided to focus on JQ1 action in the modulation of WAT lipid storage and we aimed to address whether JQ1 can also have effects on lipolysis in adipocytes. To pursue this goal, we first performed an ex vivo experiment on mouse WAT, to test if the reduced adiposity observed in vivo was due to a direct or indirect JQ1 action. Then, we assessed that this experiment was not able to clearly represent the long term JQ1 treatment, so we decided to perform an in vitro experiment where 3T3-L1 fibroblasts differentiated into adipocytes were treated with different concentrations of JQ1, for different exposure times. This allowed to find the best timing and concentration to have the highest effect of JQ1 in the modulation of the lipid storage. Then, to confirm our hypothesis, we decided to analyze the glycerol release, as it is an indicator of lipolysis. We also tried to set up different experimental conditions in which we could test JQ1 activity, giving different types of medium to the cells, with low glucose or low insulin concentration or both. The low-glucose and low-insulin content medium allowed us to better see the JQ1 role respect to the classical medium, where, instead, glucose and insulin are known to be responsible of a strong push toward anabolism, which can obscure JQ1 effect. Further investigations are needed, but the data collected so far confirm that JQ1 molecule can induce lipolysis in white adipocytes. These findings have a clear importance since they can be employed to improve clinical research concerning lipid metabolism unbalance together with new possible therapeutic strategies, as it can be at the base or a consequence of many disorders, of which obesity is a well-known example, together with other diseases like type II diabetes and hyperlipidemia.